It is well established from human and animal studies that there is a general decrease in immune function that occurs with aging. This project focuses on examining the cause(s) for this decline at the molecular level. We have shown that activation by phytohaemagglutinin (PHA) of human lymphocytes from aged individuals is impaired as demonstrated by lower 3H-thymidine incorporation, and decreased synthesis and mRNA expression of interleukin 2 (IL-2) and its receptor (IL-2R). Assessment of the same parameters of T cell activation using combined treatment with the phorbol ester PMA and the calcium ionophore A23187 revealed that elderly individuals again displayed lower 3H-thymidine incorporation but showed no impairment in the expression of IL-2 or IL-2R. PHA is a mitogen which acts nonspecifically through the T cell receptor for antigen, while PMA and A23187 bypass the surface receptor. Thus our findings suggest that the defect in IL- 2 and IL-2R expression seen in elderly individuals is associated with alterations in the cell surface antigen receptor complex rather than with a defect in the IL-2 and IL-2R gene loci or regulatory elements. Furthermore, these results indicate that additional factors other than decreased expression of IL-2 and IL- 2R are responsible the diminished proliferative capacity of lymphocytes seen as a function of aging.